Compounds useful for inhibition of farnesyl protein transferase

ABSTRACT

Novel compounds of the formula:  
                 
 
     are disclosed. In Formula 1.0 a represents N or NO, R 1  and R 3  are halo, R 2  and R 4  are independently H or halo provided that at least one is H, X is C, CH or N, and T represents a five or six membered heterocycloalkyl ring having one or two heteroatoms selected from S or O.  
     Also disclosed are methods of inhibiting farnesyl protein transferase and methods for treating tumor cells.

BACKGROUND

[0001] WO 95/10516, published Apr. 20, 1995 discloses tricycliccompounds useful for inhibiting farnesyl protein transferase.

[0002] In view of the current interest in inhibitors of farnesyl proteintransferase, a welcome contribution to the art would be compounds usefulfor the inhibition of farnesyl protein transferase. Such a contributionis provided by this invention.

SUMMARY OF THE INVENTION

[0003] This invention provides compounds useful for the inhibition offarnesyl protein transferase (FPD. The compounds of this invention arerepresented by the formula:

[0004] or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0005] a represents N or NO^(—);

[0006] R¹ and R³ are the same or different halo atom;

[0007] R² and R⁴ are selected from H and halo, provided that at leastone of R² and R⁴ is H;

[0008] the dotted line (---) represents an optional bond;

[0009] X is N, C when the optional bond is present, or CH when theoptional bond is absent;

[0010] T is a substituent selected from:

[0011] wherein:

[0012] A represents —(CH₂)_(b)—;

[0013] B represents —(CH₂)_(d)—;

[0014] b and d are independently selected from: 0, 1, 2, 3, or 4 suchthat the sum of b and d is 3 or 4; and

[0015] Y is selected from: O, S, SO, or SO₂;

[0016] wherein:

[0017] D represents —(CH₂)_(e)—;

[0018] B represents —(CH₂)_(f)—:

[0019] e and f are independently selected from: 0, 1, 2, or 3 such thatthe sum of e and f is 2 or 3; and

[0020] Z is O;

[0021] wherein:

[0022] F represents —(CH₂)_(g)—;

[0023] G represents —(CH₂)_(h)—;

[0024] H represents —(CH₂)_(i)—;

[0025] h represents 1, 2, or 3

[0026] g and i are independently selected from: 0, 1 or 2 such that thesum of h, g and i is 2 or 3; and

[0027] V and W are independently selected from O, S, SO, or SO₂;

[0028] wherein:

[0029] the dotted line (---) represents an optional bound:

[0030] k is 1 or 2 such that when the optional bond is present krepresents 1, and when the optional double bond is absent then krepresents 2;

[0031] R⁵, R⁶, R⁷ and R⁸ are the same alkyl (preferably methyl); or

[0032] R⁵ and R⁷ are the same alkyl (preferably methyl), and R⁶ and R⁸are H;

[0033] wherein:

[0034] the dotted lines (---) represent optional bonds 1 and 2 such thatoptional bonds 1 and 2 are both present, or optional bonds 1 and 2 areboth absent;

[0035] Y represents O, S, SO, or SO₂;

[0036] wherein:

[0037] Y represents O, S, SO, or SO₂;

[0038] wherein:

[0039] R⁹ is selected from: —CN, —CO₂H, or —C(O)N(R¹⁰)₂;

[0040] each R¹⁰ is the same or diferent alkyl group (preferably,methyl);

[0041] wherein:

[0042] I represents —(CH₂)_(m)—;

[0043] m represents 2 or 3;

[0044] Y represents O, S, SO, or SO₂; and

[0045] R¹¹ represents alkyl (preferably ethyl);

[0046] The compounds of this invention: (i) potently inhibit farnesylprotein transferase, but not geranylgeranyl protein transferase I, invitro; (ii) block the phenotypic change induced by a form oftransforming Ras which is a farnesyl acceptor but not by a form oftransforming Ras engineered to be a geranylgeranyl acceptor; (iii) blockintracellular processing of Ras which is a farnesyl acceptor but not ofRas engineered to be a geranylgeranyl acceptor; and (iv) block abnormalcell growth in culture induced by transforming Ras.

[0047] The compounds of this invention inhibit farnesyl proteintransferase and the farnesylation of the oncogene protein Ras. Thus,this invention further provides a method of inhibiting farnesyl proteintransferase, (e.g., ras farnesyl protein transferase) in mammals,especially humans, by the administration of an effective amount of thetricyclic compounds described above. The administration of the compoundsof this invention to patients, to inhibit farnesyl protein transferase,is useful in the treatment of the cancers described below.

[0048] This invention provides a method for inhibiting or treating theabnormal growth of cells. including transformed cells, by administeringan effective amount of a compound of this invention. Abnormal growth ofcells refers to cell growth independent of normal regulatory mechanisms(e.g., loss of contact inhibition). This includes the abnormal growthof: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2)tumor cells in which the Ras protein is activated as a result ofoncogenic mutation in another gene; and (3) benign and malignant cellsof other proliferative diseases in which aberrant Ras activation occurs.

[0049] This invention also provides a method for inhibiting or treatingtumor growth by administering an effective amount of the tricycliccompounds, described herein, to a mammal (e.g., a human) in need of suchtreatment. In particular, this invention provides a method forinhibiting or treating the growth of tumors expressing an activated Rasoncogene by the administration of an effective amount of the abovedescribed compounds. Examples of tumors which may be inhibited ortreated include, but are not limited to, lung cancer (e.g., lungadenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as,for example, exocrine pancreatic carcinoma), colon cancers (e.g.,colorectal carcinomas, such as, for example, colon adenocarcinoma andcolon adenoma), myeloid leukemias (for example, acute myelogenousleukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome(MDS), bladder carcinoma, epidermal carcinoma, breast cancer andprostate cancer.

[0050] It is believed that this invention also provides a method forinhibiting or treating proliferative diseases, both benign andmalignant, wherein Ras proteins are aberrantly activated as a result ofoncogenic mutation in other genes—i.e., the Ras gene itself is notactivated by mutation to an oncogenic form—with said inhibition ortreatment being accomplished by the administration of an effectiveamount of the tricyclic compounds described herein, to a mammal (e.g., ahuman) in need of such treatment. For example, the benign proliferativedisorder neurofibromatosis, or tumors in which Ras is activated due tomutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src,abl, lck, and fyn), may be inhibited or treated by the tricycliccompounds described herein.

[0051] The tricyclic compounds useful in the methods of this inventioninhibit or treat the abnormal growth of cells. Without wishing to bebound by theory, it is believed that these compounds may functionthrough the inhibition of G-protein function, such as ras p21, byblocking G-protein isoprenylation, thus making them useful in thetreatment of proliferative diseases such as tumor growth and cancer.Without wishing to be bound by theory, it is believed that thesecompounds inhibit ras farnesyl protein transferase, and thus showantiproliferative activity against ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION

[0052] As used herein, the following terms are used as defined belowunless otherwise indicated:

[0053] MH⁺—represents the molecular ion plus hydrogen of the molecule inthe mass spectrum:

[0054] Et (or ET)—represents ethyl (C₂H₅);

[0055] alkyl—represents straight and branched carbon chains and containsfrom one to twenty carbon atoms, preferably one to six carbon atoms;

[0056] halo-represents fluoro, chloro, bromo and iodo;

[0057] The following solvents and reagents are referred to herein by theabbreviations indicated: ethanol (EtOH); methanol (MeOH); acetic acid(HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF);trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA);1-hydroxybenzotriazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC); diisobutylaluminum hydride(DIBAL); and4-methylmorpholine (NMM).

[0058] The positions in the tricyclic ring system are:

[0059] Preferred halo atoms for R¹, R², R³, and R⁴ in Formula 1.0 areselected from: Br, Cl or I, with Br and Cl being preferred.

[0060] Compounds of Formula 1.0 include compounds of the formula:

[0061] wherein R¹ and R³ are the same or different halo. Preferably, forthese dihalo compounds, R¹ and R³ are independently selected from Br orCl, and more preferably R¹ is Br and R³ is Cl. Preferably, X is CH or N,with CH being more preferred.

[0062] Compounds of Formula 1.0 include compounds of Formulas 1.1 and1.2:

[0063] wherein R¹, R³ and R⁴ in Formula 1.1 are halo, and R¹, R² and R³in Formula 1.2 are halo. Compounds of Formula 1.1 are preferred.

[0064] Preferably, in Formula 1.1, R¹ is Br, R³ is Cl, and R⁴ is halo.More preferably, in Formula 1.1, R¹ is Br, R³ is Cl, and R⁴ is Br.

[0065] Preferably, in Formula 1.2, R¹ is Br, R² is halo, and R³ is Cl.More preferably, in Formula 1.1, R¹ is Br, R² is Br, and R³ is Cl.

[0066] Preferably, for compounds of Formulas 1.1 and 1.2, X is CH or N.For compounds of Formula 1.1, X is preferably CH.

[0067] Preferably, for the compounds of this invention, the optionalbond between positions 5 and 6 (i.e., C5-C6) in the tricyclic system isabsent.

[0068] Also, preferably, for the compounds of this invention,substituent a in Ring I represents N.

[0069] Those skilled in the art will appreciate that compounds ofFormula 1.0 include compounds of Formulas 1.3 and 1.4:

[0070] wherein X is CH or N, with compounds of 1.3 being preferred forcompounds of Formula 1.1, and with compounds of Formula 1.4 beingpreferred for componds of Formula 1.2.

[0071] Thus, compounds of the invention include compounds of theformulas:

[0072] Compounds of Formula 1.9 are preferred.

[0073] Preferably substituent T is

[0074] More preferably, substituent T is the substituent of Formula 2.0wherein the sum of b and d is 4. Most preferably b is 2 and d is 2forming the group:

[0075] Preferably, Y is O.

[0076] Examples of Formula 2.0 also include substituents wherein: (a)the sum of b and d is 3, wherein b is 3 and d is 0; (b) the sum of b andd is 4, wherein b is 4 and d is 0; (c) the sum of b and d is 4, whereinb is 3 and d is 1; and (d) the sum of b and d is 3, wherein b is 2 and dis 1. For these examples Y is preferably O.

[0077] Examples of Formula 2.0 include:

[0078] includes substituents wherein: (a) the sum of e and f is 3,wherein e is 3 and f is 0; (b) the sum of e and f is 2, wherein e is land d is 1; and (c) the sum of e and f is 2, wherein e is 2 and f is 0.

[0079] Examples of Formula 3.0 include:

[0080] includes substituents wherein: g is 0, h is 2, and i is 1.Preferably, V and W are O. For example, Formula 4.0 includes thesubstituent

[0081] includes the substituents:

[0082] includes the substituents:

[0083] Representative compounds of the invention include compounds ofthe formula:

[0084] wherein R¹² is selected from:

[0085] Those skilled in the art will appreciate that substituent R¹² isthe same as substituent

[0086] Representative compounds of this invention also include:

[0087] Representative compounds of the invention also include:

[0088] Lines drawn into the ring systems indicate that the indicatedbond may be attached to any of the substitutable ring carbon atoms.

[0089] Certain compounds of the invention may exist in differentisomeric (e.g., enantiomers and diastereoisomers) forms. The inventioncontemplates all such isomers both in pure form and in admixture,including racemic mixtures. Enol forms are also included.

[0090] Certain tricyclic compounds will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines. hydroxyalkylamines,N-methylglucamine and the like.

[0091] Certain basic tricyclic compounds also form pharmaceuticallyacceptable salts, e.g., acid addition salts. For example, thepyrido-nitrogen atoms may form salts with strong acid, while compoundshaving basic substituents such as amino groups also form salts withweaker acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonicand other mineral and carboxylic acids well known to those in the art.The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce a salt in theconventional manner. The free base forms may be regenerated by treatingthe salt with a suitable dilute aqueous base solution such as diluteaqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. Thefree base forms differ from their respective salt forms somewhat incertain physical properties, such as solubility in polar solvents, butthe acid and base salts are otherwise equivalent to their respectivefree base forms for purposes of the invention.

[0092] All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

[0093] Compounds of the invention may be prepared according to theprocedures described in WO 95/10516 published Apr. 20, 1995, U.S. Pat.No. 5,719,148 issued Feb. 17, 1998, and copending application Ser. No.08/766,601 filed Dec. 12, 1996; the disclosures of each beingincorporated herein by reference thereto; and according to theprocedures described below.

[0094] Compounds of the invention can be prepared according to thereaction:

[0095] In the reaction, the cyclic ether carboxylic acid (14.0) iscoupled to the tricyclic amine (14.0) using amide bond formingconditions well known to those skilled in the art. The substituents areas defined for Formula 1.0. For example, carbodiimide coupling methods(e.g., DEC) can be used. For example, the carboxylic acid (14.0) can bereacted with the tricyclic amine (13.0) using DEC/HOBT/NMM in DMF atabout 25° C. for a sufficient period of time, e.g., about 18 hours, toproduce a compound of Formula 1.0.

[0096] For example, using the carbodiimide coupling methods, compoundsof the invention can be produced according to the reaction:

[0097] The cyclic ether carboxylic acids (14.0) are prepared by methodswell known in the art. Commercially available cyclic ether ketones canbe reacted in a Wittig reaction to produce olefinesters. The olefin isthen reduced by catalytic hydrogenation or by metal hydride reduction tothe saturated cyclic ether acetates which are then hydrolyzed to thecyclic ether acids (14.0). See, for example, J. Med. Chem. (1993), 36,2300, the disclosure of which is incorporated herein by referencethereto. The reaction is illustrated in Scheme 1 below.

[0098] In Scheme 1, n represents 0 or 1, and Q represents O or S.

[0099] The exocyclic olefin from the Wittig reaction in Scheme 1 can bereacted with cyanide in a Michael reaction to form a nitrile, or withhydrogen peroxide to form an epoxide. The nitrile can be hydrolyzed to acarboxy group and later converted to amides. The epoxide can behydrolyzed or reduced to an alcohol. This reaction, well known to thoseskilled in the art, is illustrated in Scheme 2 below.

[0100] wherein n and Q are as defined in Scheme 1.

[0101] The cyclic ether acetates can also be produced by the insertionof an acetate carbene into a C—H bond next to the ether heteroatom of acyclic ether, as described in Tetrahedron (1989). 45, 69. The acetatecarbene can be produced from a diazoacetate, such as ethyl diazoacetate,and a rhodium or copper catalyst, such as dirhodium diacetate of coppersulfate and heat. This is illustrated by the reaction:

[0102] wherein n and Q are as defined in Scheme 1.

[0103] If the cyclic ether contains a double bond, the acetate carbenecan add to the double bond to produce a bicyclocyclic ether acetate asdescribed in Comp. Rend. (1957), 244, 2806. If the double bond isadjacent to the ether heteroatom, the resulting cyclopropyl ring can beopend by catalytic hydrogenation by an alcohol and acid. This reactionis illustrated in Scheme 3 below.

[0104] wherein n and Q are as defined in Scheme 1.

[0105] Cyclic ethers containing a carboxy group directly attached can beprepared by a base catalyzed cyclization of a dihalo ether with diethylmalonate followed by hydrolysis and decarboxylation as described in J.Am. Chem. Soc. (1995), 115, 8401. This is illustrated by Scheme 4 below.

[0106] wherein n and Q are as defined in Scheme 1.

[0107] Many bicyclic-cyclic ether ketones are known in the literature.Many of these can be made by Deils-Alder processes. For example, J. Am.Chem. Soc. (1978), 100, 1765 describes the the reaction:

[0108] These bicyclic-cyclic ether ketones can be reacted in a Wittigreaction as above to produce bicyclic-cyclic ether acetates.

[0109] Compounds of Formula 13.0a

[0110] are prepared by methods known in the art, for example by methodsdisclosed in WO 95/10516, in U.S. Pat. No. 5,151,423 and those describedbelow. Compounds of Formula 13.0a wherein X is C (when the double bondis present) or CH and the C-3 postion of the pyridine ring in thetricyclic structure is substituted by bromo (i.e., R¹ is Br) can also beprepared by a procedure comprising the following steps:

[0111] (a) reacting an amide of the formula

[0112] wherein R^(11a) is Br, R^(5a) is hydrogen and R^(6a) is C₁-C₆alkyl, aryl or heteroaryl; R^(5a) is C₁-C₆ alkyl, aryl or heteroaryl andR^(6a) is hydrogen; R^(5a) and R^(6a) are independently selected fromthe group consisting of C₁-C₆ alkyl and aryl; or R^(5a) and R^(6a),together with the nitrogen to which they are attached, form a ringcomprising 4 to 6 carbon atoms or comprising 3 to 5 carbon atoms and onehetero moiety selected from the group consisting of —O— and —NR^(9a)—,wherein R^(9a) is H, C₁-C₆ alkyl or phenyl;

[0113] with a compound of the formula

[0114] wherein R^(1a), R^(2a), R^(3a) and R^(4a) are are independentlyselected from the group consisting of hydrogen and halo and R^(7a) is Clor Br, in the presence of a strong base to obtain a compound of theformula

[0115] (b) reacting a compound of step (a) with

[0116] (i) POCl₃ to obtain a cyano compound of the formula

[0117] (ii) DIBALH to obtain an aldehyde of the formula

[0118] (c) reacting the cyano compound or the aldehyde with a piperidinederivative of the formula

[0119] wherein L is a leaving group selected from the group consistingof Cl and Br, to obtain a ketone or an alcohol of the formula below,respectively:

[0120] (d)(i) cyclizing the ketone with CF₃SO₃H to obtain a compound ofFormula 13.0a wherein the dotted line represents a double bond; or

[0121] (d)(ii) cyclizing the alcohol with polyphosphoric acid to obtaina compound of Formula 13.0a wherein the dotted line represents a singlebond.

[0122] Methods for preparing compounds of Formula 13.0a disclosed in WO95/10516, U.S. Pat. No. 5,151,423 and described below employ a tricyclicketone intermediate. Such intermediates of the formula

[0123] wherein R^(11b), R^(1a), R^(2a), R^(3a) and R^(4a) areindependently selected from the group consisting of hydrogen and halo,can be prepared by the following process comprising:

[0124] (a) reacting a compound of the formula

[0125] (i) with an amine of the formula NHR^(5a)R^(6a), wherein R^(5a)as R^(6a) are as defined in the process above; in the presence of apalladium catalyst and carbon monoxide to obtain an amide of theformula:

[0126] (ii) with an alcohol of the formula R^(10a)OH, wherein R^(10a) isC₁-C₆ lower alkyl or C₃-C₆ cycloalkyl, in the presence of a palladiumcatalyst and carbon monoxide to obtain the ester of the formula

[0127] followed by reacting the ester with an amine of formulaNHR^(5a)R^(6a) to obtain the amide;

[0128] (b) reacting the amide with an iodo-substituted benzyl compoundof the formula

[0129] wherein R^(1a), R^(2a), R^(3a), R^(4a) and R^(7a) are as definedabove, in the presence of a strong base to obtain a compound of theformula

[0130] (c) cyclizing a compound of step (b) with a reagent of theformula R^(8a)MgL, wherein R^(8a) is C₁-C₈ alkyl, aryl or heteroaryl andL is Br or Cl, provided that prior to cyclization, compounds whereinR^(5a) or R^(6a) is hydrogen are reacted with a suitable N-protectinggroup.

[0131] Compounds of Formula 1.0, wherein substituent a is NO (Ring I)and X is C or CH, can be made from compounds of Formula 13.0a usingprocedures well known to those skilled in the art. For example thecompound of Formula 13.0a can be reacted with m-chloroperoxybenzoic acidin a suitable organic solvent, e.g., dichloromethane (usually anhydrous)or methylene chloride, at a suitable temperature, to produce a compoundof Formula 13.0b

[0132] Generally, the organic solvent solution of Formula 13.0a iscooled to about 0° C. before the m-chloroperoxybenzoic acid is added.The reaction is then allowed to warm to room temperature during thereaction period. The desired product can be recovered by standardseparation means. For example, the reaction mixture can be washed withan aqueous solution of a suitable base, e.g., saturated sodiumbicarbonate or NaOH (e.g., 1N NaOH), and then dried over anhydrousmagnesium sulfate. The solution containing the product can beconcentrated in vacuo. The product can be purified by standard means,e.g., by chromatography using silica gel (e.g., flash columnchromatography).

[0133] Alternatively, compounds of Formula 1.0, wherein substituent a isNO and X is C or CH, can be made from compounds of Formula 1.0, whereinsubstituent a is N, by the m-chloroperoxybenzoic acid oxidationprocedure described above.

[0134] Also, alternatively, the compounds of Formula 1.0, whereinsubstituent a is NO and X is C or CH, can be made from tricyclic ketonecompounds

[0135] using the oxidation procedure with m-chloroperoxybenzoic acid.The oxidized intermediate compounds

[0136] are then reacted by methods known in the art to produce compoundsof the invention.

[0137] Those skilled in the art will appreciate that the oxidationreaction can be conducted on racemic mixtures and the isomers can thenbe separated by know techniques, or the isomers can be separated firstand then oxidized to the corresponding N-oxide.

[0138] Those skilled in the art will appreciate that it is preferable toavoid an excess of m-chloroperoxybenzoic acid when the oxidationreaction is carried out on the compounds having a C-11 double bond topiperidine Ring IV. In these reactions an excess ofm-chloroperoxybenzoic acid can cause epoxidation of the C-11 doublebond.

[0139] (+)-Isomers of compounds of Formula 13.0a wherein X is CH can beprepared with high enantioselectivity by using a process comprisingenzyme catalyzed transesterification. Preferably, a racemic compound ofFormula 13.0a, wherein X is C, the double bond is present and R⁴ is notH, is reacted with an enzyme such as Toyobo LIP-300 and an acylatingagent such as trifluoroethly isobutyrate; the resultant (+)-amide isthen hydrolyzed, for example by refluxing with an acid such as H₂SO₄, toobtain the corresponding optically enriched (+)-isomer wherein X is CHand R³ is not H. Alternatively, a racemic compound of Formula 13.0a,wherein X is C, the double bond is present and R⁴ is not H, is firstreduced to the corresponding racemic compound of Formula 13.0a wherein Xis CH and then treated with the enzyme (Toyobo LIP-300) and acylatingagent as described above to obtain the (+)-amide, which is hydrolyzed toobtain the optically enriched (+)-isomer.

[0140] Compounds of the invention, wherein a is NO and X is N, can beprepared from the tricyclic ketone (II) described above. Ketone (II) canbe converted to the corresponding C-11 hydroxy compound which in turncan be converted to the corresponding C-11 chloro compound

[0141] and (IV) can then be reacted with piperazine to produce theintermediate

[0142] Intermediate (V) can then be reacted with the reagents, usingtechniques well known in the art, which will provide the desiredcompound.

[0143] Compounds useful in this invention are exemplified by thefollowing examples, which should not be construed to limit the scope ofthe disclosure.

PREPARATIVE EXAMPLE 1

[0144]

[0145] Combine 14.95 g (39 mmol) of8-chloro-11-(1-ethoxy-carbonyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridineand 150 mL of CH₂Cl₂, then add 13.07 g (42.9 mmol) of (nBu)₄NNO₃ andcool the mixture to 0° C. Slowly add (dropwise) a solution of 6.09 mL(42.9 mmol) of TFAA in 20 mL of CH₂Cl₂ over 1.5 hours. Keep the mixtureat 0° C. overnight, then wash successively with saturated NaHCO₃(aqueous), water and brine. Dry the organic solution over Na₂SO₄,concentrate in vacuo to a residue and chromatograph the residue (silicagel, EtOAc/hexane gradient) to give 4.32 g and 1.90 g of the two productcompounds 1A(i) and 1A(ii), respectively. Mass Spec. for compound 1A(i):MH⁺=428.2. Mass Spec. for compound 1A(ii): MH⁺=428.3.

[0146] Combine 22.0 g (51.4 mmol) of the product 1A(i) from Step A, 150mL of 85% EtOH (aqueous), 25.85 g (0.463 mole) of Fe powder and 2.42 g(21.8 mmol) of CaCl₂, and heat at reflux overnight. Add 12.4 g (0.222mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl₂ and heat at reflux for2 hours. Add another 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8mmol) of CaCl₂ and heat at reflux for 2 hours more. Filter the hotmixture through celite®, wash the celite® with 50 mL of hot EtOH andconcentrate the filtrate in vacuo to a residue. Add 100 mL of anhydrousEtOH, concentrate to a residue and chromatograph the residue (silicagel, MeOH/CH₂Cl₂ gradient) to give 16.47 g of the product compound.

[0147] Combine 16.47 g (41.4 mmol) of the product from Step B. and 150mL of 48% HBr (aqueous) and cool to −3° C. Slowly add (dropwise) 18 mLof bromine, then slowly add (dropwise) a solution of 8.55 g (0.124 mole)of NaNO₂ in 85 mL of water. Stir for 45 minutes at −3° to 0° C., thenadjust to pH=10 by adding 50% NaOH (aqueous). Extract with EtOAc, washthe extracts with brine and dry the extracts over Na₂SO₄. Concentrate toa residue and chromatograph (silica gel, EtOAc/hexane gradient) to give10.6 g and 3.28 g of the two product compounds 1C(i) and 1C(ii),respectively. Mass Spec. for compound 1C(i): MH⁺= 461.2. Mass Spec. forcompound 1C(ii): MH⁺=539.

[0148] Hydrolyze the product 3C(i) of Step C by dissolving inconcentrated HCl and heating to about 100° C. for @ 16 hours. Cool themixture, the neutralize with 1 M NaOH (aqueous). Extract with CH₂Cl₂,dry the extracts over MgSO₄, filter and concentrate in vacuo to thetitle compound. Mass Spec.: MH⁺= 466.9.

PREPARATIVE EXAMPLE 2

[0149]

[0150] Combine 25.86 g (55.9 mmol) of4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylicacid ethyl ester and 250 mL of concentrated H₂SO₄ at −5° C., then add4.8 g (56.4 mmol) of NaNO₃ and stir for 2 hours. Pour the mixture into600 g of ice and basify with concentrated NH₄OH (aqueous). Filter themixture, wash with 300 mL of water, then extract with 500 mL of CH₂Cl₂.Wash the extract with 200 mL of water, dry over MgSO₄, then filter andconcentrate in vacuo to a residue. Chromatograph the residue (silicagel, 10% EtOAc/CH₂Cl₂) to give 24.4 g (86% yield) of the product.m.p.=165-167° C., Mass Spec.: MH⁺=506 (CI). Elemental analysis:calculated—C, 52.13; H, 4.17; N, 8.29; found—C, 52.18; H, 4.51; N, 8.16.

[0151] Combine 20 g (40.5 mmol) of the product of Step A and 200 mL ofconcentrated H₂SO₄ at 20° C., then cool the mixture to 0° C. Add 7.12 g(24.89 mmol) of 1,3-dibromo-5,5-dimethylhydantoin to the mixture andstir for 3 hours at 20° C. Cool to 0° C., add an additional 1.0 g (3.5mmol) of the dibromohydantoin and stir at 20° C. for 2 hours. Pour themixture into 400 g of ice, basify with concentrated NH₄OH (aqueous) at0° C., and collect the resulting solid by filtration. Wash the solidwith 300 mL of water, slurry in 200 mL of acetone and filter to provide19.79 g (85.6% yield) of the product. m.p.=236-237° C., Mass Spec.:MH⁺=584 (CI). Elemental analysis: calculated—C, 45.11; H. 3.44; N, 7.17;found—C, 44.95; H, 3.57; N, 7.16

[0152] Step C:

[0153] Combine 25 g (447 mmol) of Fe filings, 10 g (90 mmol) of CaCl₂and a suspension of 20 g (34.19 mmol) of the product of Step B in 700 mLof 90:10 EtOH/water at 50° C. Heat the mixture at reflux overnight,filter through Celite® and wash the filter cake with 2×200 mL of hotEtOH. Combine the filtrate and washes, and concentrate in vacuo to aresidue. Extract the residue with 600 mL of CH₂Cl₂, wash with 300 mL ofwater and dry over MgSO₄. Filter and concentrate in vacuo to a residue,then chromatograph (silica gel, 30% EtOAc/CH₂Cl₂) to give 11.4 g (60%yield) of the product. m.p.=211-212° C., Mass Spec.: MH⁺= 554 (CI).Elemental analysis: calculated—C, 47.55; H, 3.99; N, 7.56; found—C,47.45; H, 4.31; N. 7.49.

[0154] Slowly add (in portions) 20 g (35.9 mmol) of the product of StepC to a solution of 8 g (116 mmol) of NaNO₂ in 120 mL of concentrated HCl(aqueous) at −10° C. Stir the resulting mixture at 0° C. for 2 hours,then slowly add (dropwise) 150 mL (1.44 mole) of 50% H₃PO₂ at 0° C. overa 1 hour period. Stir at 0° C. for 3 hours, then pour into 600 g of iceand basify with concentrated NH₄OH (aqueous). Extract with 2×300 mL ofCH₂Cl₂, dry the extracts over MgSO₄, then filter and concentrate invacuo to a residue. Chromatograph the residue (silica gel, 25%EtOAc/hexanes) to give 13.67 g (70% yield) of the product. m.p.=163-165°C., Mass Spec.: MH⁺=539 (CI). Elemental analysis: calculated—C, 48.97;H, 4.05; N, 5.22; found—C, 48.86; H, 3.91; N, 5.18.

[0155] Combine 6.8 g (12.59 mmol) of the product of Step D and 100 mL ofconcentrated HCl (aqueous) and stir at 85° C. overnight. Cool themixture, pour it into 300 g of ice and basify with concentrated NH₄OH(aqueous). Extract with 2×300 mL of CH₂Cl₂, then dry the extracts overMgSO₄. Filter, concentrate in vacuo to a residue, then chromatograph(silica gel, 10% MeOH/EtOAc+2% NH₄OH (aqueous)) to give 5.4 g (92%yield) of the title compound. m.p.=172-174° C., Mass Spec.: MH+=467(FAB). Elemental analysis: calculated—C, 48.69; H, 3.65; N, 5.97;found—C, 48.83; H, 3.80; N, 5.97

PREPARATIVE EXAMPLE 3

[0156]

[0157] Hydrolyze 2.42 g of4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylicacid ethyl ester via substantially the same procedure as described inPreparative Example 1, Step D, to give 1.39 g (69% yield) of theproduct.

[0158] Combine 1 g (2.48 mmol) of the product of Step A and 25 mL of drytoluene, add 2.5 mL of 1 M DIBAL in toluene and heat the mixture atreflux. After 0.5 hours, add another 2.5 mL of 1 M DIBAL in toluene andheat at reflux for 1 hour. (The reaction is monitored by TLC using 50%MeOH/CH₂Cl₂+NH₄OH (aqueous).) Cool the mixture to room temperature, add50 mL of 1 N HCl (aqueous) and stir for 5 min. Add 100 mL of 1 N NaOH(aqueous), then extract with EtOAc (3×150 mL). Dry the extracts overMgSO₄, filter and concentrate in vacuo to give 1.1 g of the titlecompound.

PREPARATIVE EXAMPLE 4

[0159]

[racemic as well as (+)- and (−)-isomers]

[0160]

[0161] Combine 16.6 g (0.03 mole) of the product of Preparative Example2, Step D, with a 3:1 solution of CH₃CN and water (212.65 mL CH₃CN and70.8 mL of water) and stir the resulting slurry overnight at roomtemperature. Add 32.833 g (0.153 mole) of NaIO₄ and then 0.31 g (2.30mmol) of RuO2 and stir at room temperature give 1.39 g (69% yield) ofthe product. (The addition of RuO is accompanied by an exothermnicreaction and the temperature climbs from 20° to 30° C.) Stir the mixturefor 1.3 hrs. (temperature returned to 25° C. after about 30 min.), thenfilter to remove the solids and wash the solids with CH₂Cl₂. Concentratethe filtrate in vacuo to a residue and dissolve the residue in CH₂Cl₂.Filter to remove insoluble solids and wash the solids with CH₂Cl₂. Washthe filtrate with water, concentrate to a volume of about 200 mL andwash with bleach, then with water. Extract with 6 N HCl (aqueous). Coolthe aqueous extract to 0° C. and slowly add 50% NaOH (aqueous) to adjustto pH=4 while keeping the temperature <30° C. Extract twice with CH₂Cl₂,dry over MgSO₄ and concentrate in vacuo to a residue. Slurry the residuein 20 mL of EtOH and cool to 0° C. Collect the resulting solids byfiltration and dry the solids in vacuo to give 7.95 g of the product. ¹HNMR (CDCl₃, 200 MHz): 8.7 (s, 1H); 7.85 (m, 6H); 7.5 (d, 2H); 3.45 (m,2H); 3.15 (m, 2H).

[0162] Combine 21.58 g (53.75 mmol) of the product of Step A and 500 mLof an anhydrous 1:1 mixture of EtOH and toluene, add 1.43 g (37.8 mmol)of NaBH₄ and heat the mixture at reflux for 10 min. Cool the mixture to0° C., add 100 mL of water, then adjust to pH≈4-5 with 1 M HCl (aqueous)while keeping the temperature <10° C. Add 250 mL of EtOAc and separatethe layers. Wash the organic layer with brine (3×50 mL) then dry overNa₂SO₄. Concentrate in vacuo to a residue (24.01 g) and chromatographthe residue (silica gel, 30% hexane/CH₂Cl₂) to give the product. Impurefractions were purified by rechromatography. A total of 18.57 g of theproduct was obtained. ¹H NMR (DMSO-d₆, 400 MHz): 8.5 (s, 1H); 7.9 (s,1H); 7.5 (d of d, 2H); 6.2 (s, 1H); 6.1 (s, 1H); 3.5 (m, 1H); 3.4 (m,1H); 3.2 (m, 2H).

[0163] Combine 18.57 g (46.02 mmol) of the product of Step B and 500 mLof CHCl₃, then add 6.70 mL (91.2 mmol) of SOCl₂, and stir the mixture atroom temperature for 4 hrs. Add a solution of 35.6 g (0.413 mole) ofpiperazine in 800 mL of THF over a period of 5 min. and stir the mixturefor 1 hr. at room temperature. Heat the mixture at reflux overnight,then cool to room temperature and dilute the mixture with 1 L of CH₂Cl₂.Wash with water (5×200 mL), and extract the aqueous wash with CHCl₃(3×100 mL). Combine all of the organic solutions, wash with brine (3×200mL) and dry over MgSO₄. Concentrate in vacuo to a residue andchromatograph (silica gel, gradient of 5%, 7.5%, 10% MeOH/CH₂Cl₂+NH₄OH)to give 18.49 g of the title compound as a racemic mixture.

[0164] The racemic title compound of Step C is separated by preparativechiral chromatography (Chiralpack AD, 5 cm×50 cm column, flow rate 100mL/min., 20% iPrOH/hexane+0.2% diethylamine), to give 9.14 g of the(+)-isomer and 9.30 g of the (−)-isomer.

[0165] Physical chemical data for (+)-isomer: m.p.=74.5°-77.5° C.; MassSpec. MH⁺=471.9; [α]_(D) ²⁵=+97.4° (8.48 mg/2 mL MeOH).

[0166] Physical chemical data for (−)-isomer: m.p.=82.9°-84.5° C.; MassSpec. MH⁺=471.8; [α]_(D) ²⁵=+97.4° (8.32 mg/2mL MeOH).

PREPARATIVE EXAMPLE 5

[0167]

[0168] Combine 15 g (38.5 mmol) of4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylicacid ethyl ester and 150 mL of concentrated H₂SO₄ at −5° C., then add3.89 g (38.5 mmol) of KNO₃ and stir for 4 hours. Pour the mixture into 3L of ice and basify with 50% NaOH (aqueous). Extract with CH₂Cl₂, dryover MgSO₄, then filter and concentrate in vacuo to a residue.Recrystallize the residue from acetone to give 6.69 g of the product. ¹HNMR (CDCl₃, 200 MHz): 8.5 (s, 1H); 7.75 (s, 1H): 7.6 (s, 1H); 7.35 (s,1H); 4.15 (q, 2H); 3.8 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.8 (m, 2H);2.6-2.2 (m, 4H); 1.25 (t, 3H).

[0169] Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of85% EtOH/water, then add 0.66 g (5.9 mmol) of CaCl₂ and 6.56 g (117.9mmol) of Fe and heat the mixture at reflux overnight. Filter the hotreaction mixture through celite® and rinse the filter cake with hotEtOH. Concentrate the filtrate in vacuo to give 7.72 g of the product.Mass Spec.: MH⁺=478.0

[0170] Combine 7.70 g of the product of Step B and 35 mL of HOAc, thenadd 45 mL of a solution of Br2 in HOAc and stir the mixture at roomtemperature overnight. Add 300 mL of 1 N NaOH (aqueous), then 75 mL of50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgSO₄and concentrate in vacuo to a residue. Chromatograph the residue (silicagel, 20%-30% EtOAc/hexane) to give 3.47 g of the product (along withanother 1.28 g of partially purified product). Mass Spec.: MH⁺= 555.9.

[0171]¹H NMR (CDCl₃, 300 MHz): 8.5 (s, 1H); 7.5 (s, 1H); 7.15 (s, 1H);4.5 (s, 2H); 4.15 (m, 3H); 3.8 (br s, 2H); 3.4-3.1 (m, 4H); 9-2.75 (m,1H); 2.7-2.5 (m, 2H); 2.4-2.2 (m, 2H); 1.25 (m, 3H).

[0172] Combine 0.557 g (5.4 mmol) of t-butylnitrite and 3 mL of DMF, andheat the mixture at to 60°-70° C. Slowly add (dropwise) a mixture of2.00 g (3.6 mmol) of the product of Step C and 4 mL of DMF, then coolthe mixture to room temperature. Add another 0.64 mL of t-butylnitriteat 40° C. and reheat the mixture to 60°-70° C. for 0.5 hrs. Cool to roomtemperature and pour the mixture into 150 mL of water. Extract withCH₂Cl₂, dry the extract over MgSO₄ and concentrate in vacuo to aresidue. Chromatograph the residue (silica gel, 10%-20% EtOAc/hexane) togive 0.74 g of the product. Mass Spec.: MH⁺=541.0.

[0173]¹H NMR (CDCl₃, 200 MHz): 8.52 (s, 1H); 7.5 (d, 2H); 7.2 (s, 1H);4.15 (q, 2H); 3.9-3.7 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.5 (m, 2H); 2.4-2.2(m, 2H); 2.1-1.9 (m, 2H); 1.26 (t, 3H).

[0174] Combine 0.70 g (1.4 mmol) of the product of Step D and 8 mL ofconcentrated HCl (aqueous) and heat the mixture at reflux overnight. Add30 mL of 1 N NaOH (aqueous), then 5 mL of 50% NaOH (aqueous) and extractwith CH₂Cl₂. Dry the extract over MgSO₄ and concentrate in vacuo to give0.59 g of the title compound. Mass Spec.: M⁺=468.7. m.p.=123.9°-124.2°C.

PREPARATIVE EXAMPLE 6

[0175]

[racemic as well as (+)- and (−)-isomers]

[0176]

[0177] Prepare a solution of 8.1 g of the title compound fromPreparative Example 5. Step E, in toluene and add 17.3 mL of a 1Msolution of DIBAL in toluene. Heat the mixture at reflux and slowly add(dropwise) another 21 mL of 1 M DIBAL/toluene solution over a period of40 min. Cool the reaction mixture to about 0° C. and add 700 mL of 1 MHCl (aqueous). Separate and discard the organic phase. Wash the aqueousphase with CH₂Cl₂, discard the extract, then basify the aqueous phase byadding 50% NaOH (aqueous). Extract with CH₂Cl₂, dry the extract overMgSO₄ and concentrate in vacuo to give 7.30 g of the title compound,which is a racemic mixture of enantiomers.

[0178] The racemic title compound of Step A is separated by preparativechiral chromatography (Chiralpack AD, 5 cm×50 cm column, using 20%iPrOH/hexane+0.2% diethylamine), to give the (+)-isomer and the(−)-isomer of the title compound.

[0179] Physical chemical data for (+)-isomer: m.p.=148.8° C.; Mass Spec.MH⁺=469; [α]_(D) ²⁵=+65.6° (12.93 mg/2mL MeOH).

[0180] Physical chemical data for (−)-isomer: m.p.=112° C.; Mass Spec.MH⁺=469; [α]_(D) ²⁵=−65.2° (3.65 mg/2mL MeOH).

PREPARATIVE EXAMPLE 7

[0181]

[racemic as well as (+)- and (−)-isomers]

[0182]

[0183] Combine 40.0 g (0.124 mole) of the starting ketone and 200 mL ofH₂SO₄ and cool to 0° C. Slowly add 13.78 g (0.136 mole) of KNO₃ over aperiod of 1.5 hrs., then warm to room temperature and stir overnight.Work up the reaction using substantially the same procedure as describedfor Preparative Example 2, Step A. Chromatograph (silica gel, 20%, 30%,40%. 50% EtOAc/hexane, then 100% EtOAc) to give 28 g of the 9-nitroproduct, along with a smaller quantity of the 7-nitro product and 19 gof a mixture of the 7-nitro and 9-nitro compounds.

[0184] React 28 g (76.2 mmol) of the 9-nitro product of Step A, 400 mLof 85% EtOH/water, 3.8 g (34.3 mmol) of CaCl₂ and 38.28 g (0.685 mole)of Fe using substantially the same procedure as described forPreparative Example 2, Step C, to give 24 g of the product

[0185] Combine 13 g (38.5 mmol) of the product of Step B, 140 mL of HOAcand slowly add a solution of 2.95 mL (57.8 mmol) of Br₂ in 10 mL of HOAcover a period of 20 min. Stir the reaction mixture at room temperature,then concentrate in vacuo to a residue. Add CH₂Cl₂ and water, thenadjust to pH=8-9 with 50% NaOH (aqueous). Wash the organic phase withwater, then brine and dry over Na₂SO₄. Concentrate in vacuo to give 11.3g of the product.

[0186] Cool 100 mL of concentrated HCl (aqueous) to 0° C., then add 5.61g (81.4 mmol) of NaNO₂ and stir for 10 min. Slowly add (in portions)11.3 g (27.1 mmol) of the product of Step C and stir the mixture at0°-3° C. for 2.25 hrs. Slowly add (dropwise) 180 mL of 50% H₃PO₂(aqueous) and allow the mixture to stand at 0° C. overnight. Slowly add(dropwise) 150 mL of 50% NaOH over 30 min., to adjust to pH=9, thenextract with CH₂Cl₂. Wash the extract with water, then brine and dryover Na₂SO₄. Concentrate in vacuo to a residue and chromatograph (silicagel, 2% EtOAc/CH ₂Cl₂) to give 8.6 g of the product.

[0187] Combine 8.6 g (21.4 mmol) of the product of Step D and 300 mL ofMeOH and cool to 0°-2° C. Add 1.21 g (32.1 mmol) of NaBH₄ and stir themixture at ˜0° C. for 1 hr. Add another 0.121 g (3.21 mmol) of NaBH₄,stir for 2 hr. at 0° C., then let stand overnight at 0° C. Concentratein vacuo to a residue then partition the residue between CH₂Cl₂ andwater. Separate the organic phase and concentrate in vacuo (50° C.) togive 8.2 g of the product.

[0188] Combine 8.2 g (20.3 mmol) of the product of Step E and 160 mL ofCH₂Cl₂, cool to 0° C., then slowly add (dropwise) 14.8 mL (203 mmol) ofSOCl₂ over a 30 min. period. Warm the mixture to room temperature andstir for 4.5 hrs., then concentrate in vacuo to a residue, add CH₂Cl₂and wash with 1 N NaOH (aqueous) then brine and dry over Na2SO₄.Concentrate in vacuo to a residue, then add dry THF and 8.7 g (101 mmol)of piperazine and stir at room temperature overnight. Concentrate invacuo to a residue, add CH₂Cl₂, and wash with 0.25 N NaOH (aqueous),water, then brine. Dry over Na₂SO₄ and concentrate in vacuo to give 9.46g of the crude product. Chromatograph (silica gel, 5% MeOH/CH₂Cl₂+NH₃)to give 3.59 g of the title compound, as a racemate. ¹H NMR (CDCl₃, 200MHz): 8.43 (d, 1H); 7.55 (d, 1H); 7.45 (d, 1H); 7.11 (d, 1H); 5.31 (s,1H); 4.86-4.65 (m, 1H); 3.57-3.40 (m, 1H); 2.98-2.55 (m, 6H); 2.45-2.20(m, 5H).

[0189] The racemic title compound from Step F (5.7 g) is chromatographedas described for Preparative Example 4, Step D, using 30%iPrOH/hexane+0.2% diethylamine, to give 2.88 g of the R-(+)-isomer and2.77 g of the S-(−)-isomer of the title compound.

[0190] Physical chemical data for the R-(+)-isomer: Mass Spec.MH⁺=470.0; [α]_(D) ²⁵=+12.1° (10.9 mg/2 mL MeOH).

[0191] Physical chemical data for the S-(−)-isomer: Mass Spec.MH⁺=470.0; [α]_(D) ²⁵=+13.2° (11.51 mg/2 mL MeOH).

PREPARATIVE EXAMPLE 8

[0192]

[racemic as well as (+)- and (−)-isomers]

[0193]

[0194] Combine 13 g (33.3 mmol) of the title compound from PreparativeExample 2, Step E, and 300 mL of toluene at 20° C., then add 32.5 mL(32.5 mmol) of a 1 M solution of DIBAL in toluene. Heat the mixture atreflux for 1 hr., cool to 20° C., add another 32.5 mL of 1 M DIBALsolution and heat at reflux for 1 hr. Cool the mixture to 20° C. andpour it into a mixture of 400 g of ice, 500 mL of EtOAc and 300 mL of10% NaOH (aqueous). Extract the aqueous layer with CH₂Cl₂ (3×200 mL),dry the organic layers over MgSO₄, then concentrate in vacuo to aresidue. Chromatograph (silica gel, 12% MeOH/CH₂Cl₂+4% NH₄OH) to give10.4 g of the title compound as a racemate. Mass Spec.: MH⁺=469 (FAB).Partial ¹H NMR (CDCl₃, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H): 7.27 (d.1H): 7.06 (d, 1H), 3.95 (d, 1H).

[0195] The racemic title compound of Step A is separated by preparativechiral chromatography (Chiralpack AD, 5 cm×50 cm column, using 5%iPrOH/hexane+0.2% diethylamine), to give the (+)-isomer and the(−)-isomer of the title compound.

[0196] Physical chemical data for (+)-isomer: Mass Spec. MH⁺=469 (FAB);[α]_(D) ²⁵=+43.5° (c=0.402, EtOH); partial ¹H NMR (CDCl₃, 400 MHz): 8.38(s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1H); 3.95 (d, 1H).

[0197] Physical chemical data for (−)-isomer: Mass Spec. MH⁺=469 (FAB);[α]_(D) ²⁵=−41.8° (c=0.328 EtOH); partial ¹H NMR (CDCl₃, 400 MHz): 8.38(s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1H); 3.95 (d, 1H).

PREPARATIVE EXAMPLE 9

[0198]

[racemic as well as R-(+)- and S-(−)-isomers]

[0199] The compound

[0200] is prepared according to the procedures of Preparative Example 40of WO 95/10516 (published Apr. 20, 1995), by following the proceduresdescribed in Example 193 of WO 95/10516.

[0201] The (+)- and (−)-isomers can be separated by followingessentially the same procedure as Step D of Preparative Example 4.

[0202] Physical chemical data for the R-(+)-isomer: ¹³C NMR (CDCl₃):155.8 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3 (C);133.4 (C); 132.0 (CH); 129.9 (CH); 125.6 (CH); 119.3 (C); 79.1 (CH);52.3 (CH₂); 52.3 (CH); 45.6 (CH₂); 45.6 (CH₂); 30.0 (CH₂); 29.8 (CH₂).[α]_(D) ²⁵=+25.8° (8.46 mg/2 mL MeOH).

[0203] Physical chemical data for the S-(−)-isomer: ¹³C NMR (CDCl₃):155.9 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3 (C);133.3 (C); 132.0 (CH); 129.9 (CH); 125.5 (CH); 119.2 (C); 79.1 (CH);52.5 (CH₂); 52.5 (CH); 45.7 (CH₂); 45.7 (CH₂); 30.0 (CH₂); 29.8 (CH₂).[α]_(D) ²⁵=−27.9° (8.90 mg/2 mL MeOH).

PREPARATIVE EXAMPLE 10 Ethyl tetrahydropyran-4-ylidenylacetate (15.0),and ethyl 5,6-dihydro-2H-pyran-4-acetate (16.0)

[0204]

[0205] Following the chemistry described in J. Med. Chem., (1993), 36,2300, a 2 L three-neck flask equipped with a thermometer, additionfunnel and a nitrogen inlet tube and a magnetic stirrer was flame driedand charged with 1.0 L of anhydrous 1,2-dimethoxyethane and 9.0 g (0.38mol) of sodium hydride (60% dispersion in oil). Triethylphosphono-acetate, 56 g (0.25 mol), was added, dropwise with sirring, atsuch a rate that the reaction temperature was maintained at 20-25° C.After addition, the reaction was stirred at 25° C. for 45 min. then 25 g(0.25 mol) of tetrahydro-4H-pyran-4-one was added dropwise while keepingthe reaction temperature at 20-25° C. by cooling with an ice bath. Afteraddition, the reaction was refluxed for one hour, cooled to roomtemperature and then poured into 4 L of ice water. This was extractedwith three 2 L portions of ether. The combined ether layers were driedover magnesium sulfate and concentrated under vacuum giving 27 g of ayellow oil that is a 1:1.4 mixture of 15.0 and 16.0 as determined byNMR.

[0206] Sixteen grams of the above oil were flash chromatographed on 1.5Kg of silica gel using ethyl acetate-hexane, 10-90, and collecting 200mL fractions. Fractions 13-22 yielded 5.65 g of pure 15.0, ethyltetrahydropyran-4-ylidenyl-acetate, and fractions 31-50 yielded 8.06 gof pure 16.0, ethyl 5,6-dihydro-2H-pyran-4-acetate.

PREPARATIVE EXAMPLE 11 Ethyl tetrahydropyran-4-acetate

[0207]

[0208] A mixture of 15.0 and 16.0 (3 g, 17.6 mmol) from PreparativeExample 10 was dissolved in 20 mL of ethyl acetate containing 1.0 g of10% paladium on carbon. This mixture was stirred for 18 hours under anatmosphere of hydrogen. The catalyst was filtered and the filtrate wasconcentrated under vacuum giving 3.04 g of the title product as acolorless oil.

PREPARATIVE EXAMPLE 12 Ethyl tetrahydrothiopyran-4-ylidenylacetate

[0209]

[0210] Following the procedure of Preparative Example 10, but using 2.32g (20 mmol) of tetrahydrothiopyran-4-one instead oftetrahydropyran-4-one, 3.53 g of the product was obtained as a colorlessoil.

PREPARATIVE EXAMPLE 13 Ethyl tetrahydrothiopyran-4-acetate

[0211]

[0212] Ethyl tetrahydrothiopyran-4-ylidenylacetate (2.3 g, 12.4 mmol),from Preparative Example 12, was dissolved in 25 mL of ethanolcontaining 2.34 g (61.8 mmol) of sodium borohydride. After stirring for24 hours at 25° C., an additional 1.2 g of sodium borohydride was addedand the reaction was stirred for an additional 24 hours. Two additional1.2 g portions of sodium borohydride were added followed by stirring for24 hours after each addition. Silica gel TLC using hexane-ethyl acetate(95-5) showed the reaction to be complete. The reaction was treated with200 mL of water and stirred for 5 minutes. The mixture was thenextracted with three 150 mL portions of ethyl acetate. The combinedorganic layers were dried over magnesium sulfate and concentrated undervacuum giving 1.6 g of a colorless oil. The oil was chromatographed on325 mL of silica gel using hexane-ethyl acetate (98-2) and 125 mLfractions were collected. Fractions 2-15 yielded 0.24 g of the productas a colorless oil.

PREPARATIVE EXAMPLE 14 Ethyl 2′-(1,4-dioxanyl)-acetate

[0213]

[0214] Following a procedure described in Tetrahedron (1989), 45, 69, a125 mL three-neck flask equiped with an addition funnel, condenser and amagnetic stirrer was charged with 25 mL of anhydrous 1,4-dioxane and0.05 g of dirhodium diacetate. This was refluxed under nitrogen and asolution of 2.0 g (17.5 mmol) of ethyl diazoacetate in 20 mL ofanhydrous 1,4-dioxane was added dropwise over a period of 130 minutes.After addition was complete, the reaction was allowed to cool to 25° C.and filtered through a short pad of alumina and concentrated undervacuum. The residue was vacuum distilled (short path head) and the thefraction having a bp of 61°-68° C. at 0.5 mm Hg was collected, giving1.5 g of the product as a colorless oil.

PREPARATIVE EXAMPLE 15 Ethyl tetrahydrofuran-2-acetate

[0215]

[0216] Following the procedure of Preparative Example 14, 2.0 g (17.5mmol) of ethyl diazo acetate was reacted with tetrahydrofuran to give1.7 g of the product as a colorless oil, bp 84°-86° C. at 20 mm Hg.

PREPARATIVE EXAMPLE 16 Ethyl tetrahydropyran-2-acetate

[0217]

[0218] Following the procedure of Preparative Example 14, 2.0 g (17.5mmol) of ethyl diazo acetate was reacted with tetrahydropyran to give1.75 g of the product as a colorless oil, bp 95°-106° C. at 20 mm Hg.

PREPARATIVE EXAMPLE 17 Ethyl 2-oxabicyclo[4.1.0]heptane-7-exo-acetate(18.01 and Ethyl 2-oxabicyclo[4.1.0]heptane-7-endo-acetate (19.0)

[0219]

[0220] Following a procedure described in Comp. Rend. (1957), 244, 2806,a 100 mL three-neck flask equiped with an addition funnel, condenser anda magnetic stirrer was charged with 27.37 g (300 mmole) of3,4-dihydro-2H-pyran and 0.08 g of anhydrous copper II sulfate. This wasrefluxed under nitrogen and a solution of 11.42 g (100 mmole) of ethyldiazo-acetate and 8.41 g (100 mmol) of 3,4-dihydro-2H-pyran was addeddropwise over a 60 minute period. After addition was complete, thereaction was refluxed for an additional 2 hours and then allowed to coolto 25° C. This mixture was filtered through a short pad of alumina andconcentrated under vacuum. The residue was flash chromatographed onsilica gel using hexane-ethyl acetate (60-40) giving 10 g of the productas a colorless oil. Silca gel TLC Rf= 0.48 using the abovechromatography solvent. NMR shows a mixture of 18.0 and 19.0 in an 15%to 85% ratio.

PREPARATIVE EXAMPLE 18 Ethyl 3-oxabicyclo[3.1.0]hexane-6-exo-acetate[20.0] and Ethyl 3-oxabicyclo[3.1.0]hexane-6-endo-acetate (21.0)

[0221]

[0222] Following the procedure of Preparative Example 17, react 11.42 g(100 mmole) of ethyl diazo acetate with 2,5-dihydrofuran to give 4 g ofthe product as a colorless oil. Silica gel TLC Rf= 0.85 (hexane-ethylacetate 60-40).

PREPARATIVE EXAMPLE 19 Ethyl 2-oxabicyclo[3.1.0]hexane-6-exo-acetate(22.0) and Ethyl 2-oxabicyclo[3.1.0]hexane-6-endo-acetate (23.0)

[0223]

[0224] Following the procedure of Preparative Example 17, react 11.42 g(100 mmole) of ethyl diazo acetate with 2,3-dihydrofuran to give 10.4 gof the product as a colorless oil. Silica gel TLC Rf= 0.91 (hexane-ethylacetate 60-40).

PREPARATIVE EXAMPLE 20 Ethyl 4-H-pyran-4-ylidenylacetate

[0225]

[0226] Following the procedure of Preparative Example 10 but using 5 g(52 mmol) of 4-H-pyran-4-one instead of tetrahydropyran-4-one, obtain0.4 g of the product as a yellow solid, mp= 116.5-118.7, after flashsilica gel chromatography using ethyl acetate-hexane 20%-80%.

PREPARATIVE EXAMPLE 21 Ethyl tetrahydropyran-3-acetate

[0227]

[0228] Following a procedure described in Comp. Rend. (1957), 244, 2806,if one were to hydrogenate the products of Preparative Example 17 at 750psi and 100° C. using Raney nickle as the catalyst then one would obtainthe product.

PREPARATIVE EXAMPLE 22 Ethyl tetrahydrofuran-3-acetate

[0229]

[0230] Following a procedure described in Comp. Rend. (1957), 244, 2806,if one were to hydrogenate the products of Preparative Example 19 at 750psi and 100° C. using Raney nickle as the catalyst then one would obtainthe product.

PREPARATIVE EXAMPLE 23 Ethyl2,6-dimethyltetrahydropyran-4-ylidenylacetate

[0231]

[0232] Following the procedure of Preparative Example 10, if one were toreact 2,6-dimethyltetrahydro-4H-pyran-4-one (Recueil. (1959) 78, 91)with sodium hydride and triethyl phosphonoacetate to then one wouldobtain the product.

PREPARATIVE EXAMPLE 24 Ethyl 2,6-dimethyltetrabydropyran-4-acetate

[0233]

[0234] Following the procedure of Preparative Example 11, if one were tohydrogenate the product of Preparative Example 23 one would obtain theproduct.

PREPARATIVE EXAMPLE 25 Ethyl2,2,6,6-tetramethyltetrahydropyran-4-ylidenylacetate

[0235]

[0236] Following the procedure of Preparative Example 10, if one were toreact 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (J. Chem. Soc. (1944)338) with sodium hydride and triethyl phosphonoacetate then one wouldobtain the product.

PREPARATIVE EXAMPLE 26 Ethyl2,2,6,6-tetramethyltetrahydropvran-4-acetate

[0237]

[0238] Following the procedure of Preparative Example 11, if one were tohydrogenate the product of Preparative Example 25 one would obtain tothe product.

PREPARATIVE EXAMPLE 27 Ethyl tetrahydropyran-4-acetate

[0239]

[0240] Following a procedure described in Liebigs Ann. Chem. (1982) 250,if one were to react ethyl tetrahydro-4-ylidenylcarboxylate, product15.0 of Preparative Example 10, with an excess of sodium cyanide at80-100° C. one would obtain the product.

PREPARATIVE EXAMPLE 28 Ethyl8-oxabicyclo[3.2.1]octa-6-ene-3-ylidenylacetate

[0241]

[0242] Following the procedure of Preparative Example 10, if one were toreact 8-Oxabicyclo[3.2.1]octa-6-ene-3-one (J. Am. Chem. Soc. (1978)100,1765) with sodium hydride and triethyl phosphonoacetate one wouldobtain the product.

PREPARATIVE EXAMPLE 29 Ethyl 8-oxabicyclo[3.2.1]octa-6-ene-3-β-acetate(24.0) and Ethyl 8-oxabicyclo[3.2.1]octa-6-ene-3-α-acetate (25.0)

[0243]

[0244] Following the procedure of Preparative Example 11, if one were tohydrogenate the product of Preparative Example 28 one would obtain theproducts after separation by silica gel chromatography.

PREPARATIVE EXAMPLE 30 Ethyl 2-ethoxytetrahydropyran-3-acetate

[0245]

[0246] Following a procedure described in Comp. Rend. (1957), 244, 2806,if the products of Preparative Example 9 were to be reacted with boilingethanol containing 1-2% HCl gas then the product would be obtained.

PREPARATIVE EXAMPLE 31 Ethyl 2-ethoxytetrahydrofuran-3-acetate

[0247]

[0248] Following a procedure described in Comp. Rend. (1957), 244, 2806,if the products of Preparative Example 14 were to be reacted withboiling ethanol containing 1-2% HCl gas then the product would beobtained.

PREPARATIVE EXAMPLE 32 Tetrahydropyran-4-acetic acid

[0249]

[0250] The product of Preparative Example 11 (3.04 g, 17.7 mmol) wasdissoloved in 90 mL of ethanol containing 3 g (53 mmol) of potassiumhydroxide. This was stirred for 18 hours and then concentrated undervacuum. The residue was dissolved in 15 mL of water, adjusted to pH 2with 12 N HCl, and extracted with three 50 mL portions ofdichloromethane. The combined organic layers were dried over magnesiumsulfate and concentrated under vacuum giving 2.04 g of the product as awhite solid, mp=60-63° C.

[0251] Using the hydrolysis procedure of Preparative Example 32, theesters of Preparative Examples 10-20 were hydrolyzed to the carboxylicacids identified as Preparative Examples 33 to 46 in Table 1. If onewere to follow the hydrolysis procedure of Preparative Example 32, theesters of Preparative Examples 21 to 31 could be hydrolyzed to obtainthe carboxylic acids identified as Preparative Examples 47-59 inTable 1. TABLE 1 Starting Material (Ester) Product (Carboxylic Acid)

Preparative Example 10 Preparative Example 33

Preparative Example 10 Preparative Example 34

Preparative Example 12 Preparative Example 35

Preparative Example 13 Preparative Example 36

Preparative Exampel 14 Preparative Example 37

Preparative Example 15 Preparative Example 38

Preparative Example 16 Preparative Example 39

Preparative Example 17 Preparative Example 40

Preparative Example 17 Preparative Example 41

Preparative Example 18 Preparative Example 42

Preparative Example 18 Preparative Example 43

Preparative Example 19 Preparative Example 44

Preparative Example 19 Preparative Example 45

Preparative Example 20 Preparative Example 46

Preparative Example 21 Preparative Example 47

Preparative Example 22 Preparative Example 48

Preparative Example 23 Preparative Example 49

Preparative Example 24 Preparative Example 50

Preparative Example 25 Preparative Example 51

Preparative Example 26 Preparative Example 52

Preparative Example 27 Preparative Example 53

Preparative Example 27 Preparative Example 54

Preparative Example 28 Preparative Example 55

Preparative Example 29 Preparative Example 56

Preparative Example 29 Preparative Example 57

Preparative Example 30 Preparative Example 58

Preparative Example 31 Preparative Example 59

PREPARATIVE EXAMPLE 60 2-Oxabicyclo[2.2.2]-5-anti-carboxylic acid

[0252]

[0253] Ethyl 2-oxabicyclo[2.2.2]-5-anti-carboxylate (a by-productproduced along with5-anti-carbomethoxy-7-anti-acetoxy-2-oxabicyclo[2.2.2]octane describedin Tet. Lett. (1979) 35, 3275) was hydrolyzed following the procedure ofPreparative Example 32 to give the product as a waxy solid.

EXAMPLE 1 (+)-4-(3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-11(R)-yl-1-[(tetrahydro-4H-pyran-4-yl)acetylpiperidine

[0254]

[0255] Dissolve the (+) product of Preparative Example 6, Step B, (0.1g, 0.212 mmol) in 5 mL of DMF, stir at room temperature and add 0.043 g(0.424 mmol) of 4-methylmorpholine, 0.053 g (0.0276 mmol) of DEC, 0.037g (0.276 mmol) of HOBT and 0.0397 g (0.276 mmole) of the product ofPreparative Example 32. Stir the mixture at room temperature for 18hours, then concentrate in vacuo to a residue and partition betweenmethylene chloride and water. Wash the organic phase with aqueous sodiumbicarbonate solution then brine. Dry the organic phase over magnesiumsulfate, filter and concentrate in vacuo to a residue. Chromatograph theresidue on a silica gel plate, eluting with methylene chloride-methanol(96%-4%) to yield the product (0.13 g) as a white solid. M.p.=83.2-88.7°C., Mass Spec.: MH+=597. [α]_(D) ^(23.2° C.)=+55.5°, c=0.2, methylenechloride.

[0256] Using the coupling procedure of Example 1, the acids ofPreparative Examples 33-60 are reacted with the (+) product ofPreparative Example 6, Step B, to produce the compounds of Formula 1.16:

[0257] wherein R¹² is as defined in Table 2 below. In Table 2, “EX”stands for Example, and “mp” stands for melting point: TABLE 2 EX R¹² mp(° C.)  1

83.2-88.7  2

103.3-107.9  3

110.3-113.9  4

—  5

115.9-119.9  6

111-124 (d)  7

107-115 (d)  8

116-122 (d)  9

125.8-127.3 10

— 11

124.9-127.8 12

— 13

124.3-125.3 14

— 15

174.3-178.8 16

— 17

— 18

— 19

— 20

— 21

— 22

— 23

— 24

— 25

— 26

— 27

— 28

— 29

152-164 (d) Isomer 1 30

151-159 (d) Isomer 2 31

118.1-122.3 Starting acid is commerically available 32

— Starting acid described in J. Am. Chem. Soc (1995) 115, 8401

EXAMPLE 33

[0258]

[0259] Following the procedure of Example 1, react the R-(+)-isomer ofPreparative Example 9 with the product of Preparative Example 32 to givethe product as a white solid mp=93.5-97.6° C.

EXAMPLE 34

[0260]

[0261] If the the coupling procedure described in Example 1 were to beused, the product of Example 23 could be reacted with ammonium chlorideto produce the product.

EXAMPLE 35

[0262]

[0263] Dissolve 90 mg (0.14 mmol) of the product of Example 5 in 5 mL ofTHF and 34 mL of trifluoroacetic acid. Add 37 mL of 30% hydrogenperoxide and stir for three days. Concentrate under vacuum and partitionthe residue between water and dichloromethane. Dry the organic layerover magnesium sulfate, concentrate under vacuum and chromatograph theresidue by preparative silica gel TLC using dichloromethane saturatedwith ammonia to give the product as a white solid. M.p.=135.6-140° C.,Mass Spec.: MH+=628.

EXAMPLE 36

[0264]

[0265] Dissolve the (+) product of Preparative Example 6, Step B (0.5 g,1.06 mmol) in 10 mL of dichloromethane, stir at room temperature and add0.128 g (1.27 mmol) of 4-methylmorpholine, 0.285 g (1.48 mmol) of DEC,0.172 g (1.27 mmol) of HOBT and 0.097 g (1.27 mmole) of glycolic acid.Stir the mixture at room temperature for 18 hours, then concentrate invacuo to a residue and partition between methylene chloride and water.Wash the organic phase with aqueous sodium bicarbonate solution thenbrine. Dry the organic phase over magnesium sulfate, filter andconcentrate in vacuo to a residue. Chromatograph the residue bypreparative silica gel TLC, eluting with methylene chloride-methanol(95%-5%) to yield the amide of glycolic acid and the starting tricyclicreactant of Preparative Example 6.

[0266] Step B

[0267] Dissolve 0.34 g (0.643 mmol) of the product of Step A in 1 mL ofdichloromethane containing 5.4 mL of thionyl chloride. Allow to stir for18 hours and concentrate under vacuum. Add 10 mL of toluene to theresidue and concentrate under vacuum and repeat this step two additionaltimes to give the product.

[0268] Step C

[0269] Dissolve the product of Step B in 1.0 mL of dichloromethanefollowed by 0.124 g of morpholine. Stir for 18 hours then concentrateunder vacuum. Partition the residue between dichloromethane and aqueoussodium bicarbonate solution. Concentrate the organic layer under vacuumand chromatograph the residue by preparative silica gel TLC usingmethylene chloride-methanol (95%-5%) to yield the product as a whitesolid. M.p=112.4-113.5° C., Mass. Spec.: MH+=599.

EXAMPLE 37

[0270]

[0271] Following the procedure of Example 36, thiomorpholine was usedinstead of morpholine in Step C to yield the product as a white solid.

EXAMPLE 38

[0272]

[0273] Following the procedure of Example 36, except in Step A the (−)product of Preparative Example 4 Step D was used instead of the (+)product of Preparative Example 6, Step B, and thiomorpholine was usedinstead of morpholine in Step C, to yield the product as a white solid.

EXAMPLE 39

[0274]

[0275] The product of Example 38 was reacted under the conditions ofExample 35 to yield the product as a white solid.

EXAMPLE 40

[0276]

[0277] Dissolve 160 mg (0.268 mmol) of the product of Example 1 in 3 mLof CH₂Cl₂ and add 162.3 mg (0.536 mmol) of 4-chloroperoxybenzoic acid(57% pure) and stir for 3 hr. Dilute with 50 mL of CH₂Cl₂ then wash withsaturated NaHCO₃ followed by brine. Dry the organic layer over MgSO₄,concentrate in vacuo and purify the residue by preparative silica gelTLC using 2% methanol in CH₂Cl₂ saturated with ammonia to give 116 mg(71%) of the title compound as a white solid. m.p.=141-151° C. (dec); MSMH+= 613.

ASSAYS

[0278] FPT IC₅₀ (inhibition of famesyl protein transferase, in vitroenzyme assay) and COS Cell IC₅₀ (Cell-Based Assay) were determinedfollowing the assay procedures described in WO 95/10516, published Apr.20, 1995. GGPIT IC₅₀ (inhibition of geranylgeranyl protein transferase,in vitro enzyme assay), Cell Mat Assay, and anti-tumor activity (in vivoanti-tumor studies) could be determined by the assay proceduresdescribed in WO 95/10516. The disclosure of WO 95/10516 is incorporatedherein by reference thereto.

[0279] Additional assays can be carried out by following essentially thesame procedure as described above, but with substitution of alternativeindicator tumor cell lines in place of the T24-BAG cells. The assays canbe conducted using either DLD-1-BAG human colon carcinoma cellsexpressing an activated K-ras gene or SW620-BAG human colon carcinomacells expressing an activated K-ras gene. Using other tumor cell linesknown in the art, the activity of the compounds of this inventionagainst other types of cancer cells could be demonstrated.

[0280] Soft Agar Assay:

[0281] Anchorage-independent growth is a characteristic of tumorigeniccell lines. Human tumor cells can be suspended in growth mediumcontaining 0.3% agarose and an indicated concentration of a farnesyltransferase inhibitor. The solution can be overlayed onto growth mediumsolidified with 0.6% agarose containing the same concentration offarnesyl transferase inhibitor as the top layer. After the top layer issolidified, plates can be incubated for 10-16 days at 37° C. under 5%CO₂ to allow colony outgrowth. After incubation, the colonies can bestained by overlaying the agar with a solution of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolylblue) (1 mg/mL in PBS). Colonies can be counted and the IC₅₀'s can bedetermined.

[0282] The results are given in Table 3. In Table 3, “nM” representsnanomolar. TABLE 3 Compound of FPT IC₅₀ COS Cell IC₅₀ Example No. (nM)(nM) 1 0.4 1.8 1.2 12 2.4 15 2 5.5 285 3 6.1 — 5 3.5 143 6 23 — 7 42 — 82.0 68 29 6.7 30 30 7.5 75 33 45 — 35 2.3 — 36 3.1 — 37 4.9 <10 39 4.768 40 2.2 100% @ 10

[0283] The compound of Example 40 had a Soft Agar IC₅₀ of 8 nM.

[0284] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules. capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

[0285] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

[0286] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection.

[0287] Liquid form preparations may also include solutions forintranasal administration.

[0288] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

[0289] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0290] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0291] Preferably the compound Is administered orally.

[0292] Preferably, the pharmaceutical preparation is in unit dosageform. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

[0293] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg. to 300 mg, according to the particular application.

[0294] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

[0295] The amount and frequency of administration of the compounds ofthe invention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in two to four divided doses to blocktumor growth. The compounds are non-toxic when administered within thisdosage range.

[0296] The following are examples of pharmaceutical dosage forms whichcontain a compound of the invention. The scope of the invention in itspharmaceutical composition aspect is not to be limited by the examplesprovided.

Pharmaceutical Dosage Form Examples EXAMPLE A

[0297] Tablets No. Ingredients mg/tablet mg/tablet 1. Active compound100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 40 as a10% paste in Purified Water 4. Corn Starch, Food Grade 45 40 5.Magnesium Stearate 3 7 Total 300 700

Method of Manufacture

[0298] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.Granulate the mixture with Item No. 3. Mill the damp granules through acoarse screen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules.Screen the dried granules if necessary and mix with Item No. 4 and mixfor 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B

[0299] Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4.Magnesium Stearate NF 7 7 Total 253 700

Method of Manufacture

[0300] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes.Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

[0301] While the present invention has been described in conjunctionwith the specific embodiments set forth above, many alternatives,modifications and variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: arepresents N or NO^(—); R¹ and R³ are the same or different halo atom;R² and R⁴ are selected from H and halo, provided that at least one of R²and R⁴ is H; the dotted line (---) represents an optional bond; X is N,C when the optional bond is present, or CH when the optional bond isabsent; T is a substituent selected from:

wherein: A represents —(CH₂)_(b)—; B represents —(CH₂)_(d)—; b and d areindependently selected from: 0, 1, 2, 3, or 4 such that the sum of b andd is 3 or 4; and Y is selected from: O, S, SO, or SO₂;

wherein: D represents —(CH₂)_(e)—; B represents —(CH₂)_(f)—; e and f areindependently selected from: 0, 1, 2, or 3 such that the sum of e and fis 2 or 3; and Z is O;

wherein: F represents —(CH₂)_(g)—; G represents —(CH₂)_(h)—; Hrepresents —(CH₂)_(i)—; h represents 1, 2, or 3 g and i areindependently selected from: 0, 1 or 2 such that the sum of h, g and iis 2 or 3; and V and W are independently selected from O, S, SO, or SO₂;

wherein: the dotted line (---) represents an optional bound; k is 1 or 2such that when the optional bond is present k represents 1, and when theoptional double bond is absent then k represents 2; R⁵, R⁶, R⁷ and R⁸are the same alkyl (preferably methyl); or R⁵ and R⁷ are the same alkyl(preferably methyl), and R⁶ and R⁸ are H;

wherein: the dotted lines (---) represent optional bonds 1 and 2 suchthat optional bonds 1 and 2 are both present, or optional bonds 1 and 2are both absent; Y represents O, S, SO, or SO₂;

wherein: Y represents O, S, SO, or SO₂;

wherein: R⁹ is selected from: —CN, —CO₂H, or —C(O)N(R¹⁰)₂; each R¹⁰ isthe same or diferent alkyl group (preferably, methyl);

wherein: I represents —(CH₂)_(m)—; m represents 2 or 3; Y represents O,S, SO, or SO₂; and R¹¹ represents alkyl;


2. The compound of claim 1 having the formula:


3. The compound of claim 1 wherein R¹ is halo, R² is H, R³ is halo, andR⁴ is H.
 4. The compound of claim 3 wherein R¹ is Br and R³ is Cl. 5.The compound of claim 4 wherein X is CH, a is N, and the C5-C6 doublebond is absent.
 6. The compound of claim 1 wherein R¹ is halo, R² ishalo, R³ is halo, and R⁴ is H; or R¹ is halo, R² is H, R³ is halo, andR⁴ is halo.
 7. The compound of claim 6 wherein X is CH or N.
 8. Thecompound of claim 7 wherein X is CH.
 9. The compound of claim 7 whereina is N, and the C5-C6 double bond is absent.
 10. The compound of claim 9wherein R¹ is Br, R² is Br, R³ is Cl, and R⁴ is H; or R¹ is Br, R² is H,R³ is Cl, and R⁴ is Br.
 11. The compound of claim 10 wherein X is CH.12. The compound of claim 11 wherein R¹ is Br, R² is H, R³ is Cl, and R⁴is Br.
 13. The compound of claim 12 having the formula:


14. The compound of claim 13 wherein T is


15. The compound of claim 14 wherein T is


16. The compound of claim 1 having the formula:

wherein R¹² is selected from:


15. The compound of claim 14 wherein R¹² is


16. The compound of claim 1 selected from:


17. The compound of claim 1 having the formula:


18. A method of treating tumor cells expressing an activated rasoncogene comprising administering an effective amount of a compound ofclaim 1 .
 19. The method of claim 18 wherein the tumor cells treated arepancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells,thyroid follicular tumor cells, myelodysplastic tumor cells, epidermalcarcinoma tumor cells, bladder carcinoma tumor cells, colon tumorscells, breast tumor cells and prostate tumor cells.
 20. A method oftreating tumor cells wherein the Ras protein is activated as a result ofoncogenic mutation in genes other than the Ras gene, comprisingadministering an effective amount of a compound of claim 1 .
 21. Amethod of inhibiting farnesyl protein transferase comprising theadministration of an effective amount of the compound of claim 1 .
 22. Apharmaceutical composition for inhibiting farnesyl protein transferasecomprising an effective amount of compound of claim 1 in combinationwith a pharmaceutically acceptable carrier.